title: Novel MNX1 mutations and clinical analysis of familial and sporadic Currarino cases.
abstract: Currarino Syndrome (CS) is a rare congenital malformation characterized by three major clinical aspects: sacral anomalies, anorectal malformation and presacral mass. In familial settings the disorder is transmitted as autosomal dominant trait, with a wide phenotype variability and low penetrance. The causative gene of CS is the motor neuron and pancreas homeobox-1 (MNX1), mapped at 7q36, and coding for a transcription factor. Mutations in the MNX1 have been implicated in almost all familial but only in 30% of sporadic cases. In our cohort of 28 CS cases, 8 were familiar, 18 were sporadic and 2 were not determined cases. We performed mutational analysis of MNX1 in all cases by DNA sequencing as well as by Multiplex Ligation-dependent Probe Amplification (MLPA) in those CS cases where no MNX1 mutations were found, to exclude a MNX1 heterozygous loss. We identified 10 novel and 4 recurrent mutations. Among the novel mutations, 2 were frameshift variants (p.Ser4IlefsX52, p.Phe248SerfsX35), 6 were missense variants (p.Pro27Leu, p.Gly103Arg, p.Leu254Pro, p.Leu278Pro, p.Glu282Lys, p.Arg292Gly), one was a non-sense variant (p.Lys297X), and the last one was a synonymous variant (p.Gln290Gln). Mutated patients showed a variability of phenotypes but all share at least the association of sacral agenesis and presacral mass, and this co-occurrence can constitute a pathognomonic sign to perform MNX1 analysis. Genetic heterogeneity could be a possible explanation for some of the sporadic not mutated patients even if a mis-diagnosis could not be excluded. Finally, we provide an up-date of the more recent literature, reporting a total number of 82 MNX1-CS related mutations.
authors.affiliation: U.O.C. Neurochirurgia, Istituto Giannina Gaslini, Via G. Gaslini 5, Genova 16147, Italy. Electronic address: elisamerello@ospedale-gaslini.ge.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Merello
authors.forename: Patrizia
authors.initials: P
authors.lastname: De Marco
authors.forename: Marcello
authors.initials: M
authors.lastname: Ravegnani
authors.forename: Giovanna
authors.initials: G
authors.lastname: Riccipetitoni
authors.forename: Armando
authors.initials: A
authors.lastname: Cama
authors.forename: Valeria
authors.initials: V
authors.lastname: Capra
mesh_terms: D001003:Anal Canal / Q000002:abnormalities*; D015331:Cohort Studies; D004065:Digestive System Abnormalities / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D012007:Rectum / Q000002:abnormalities*; D012447:Sacrum / Q000002:abnormalities*; D013595:Syringomyelia / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C490003:MNX1 protein, human; D014157:Transcription Factors
keywords: Currarino Syndrome; MLPA analysis; MNX1 mutational analysis